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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of first generation plasminogen activators, urokinase, streptokinase and tissue plasminogen activator has revolutionized thrombolytic therapy for myocardial infarction and ischaemia, and potentially stroke. However, thrombolytic therapy employing these activators is limited by reocclusion of the very arteries being opened, which follows in a small but significant number of patients. The development of second generation plasminogen activators, e.g. staphylokinase and anisoylated plasminogen streptokinase activator complex, has not alleviated the problems encountered with classical plasminogen activators. It is now widely recognized that aberrant platelet aggregation induced primarily by thrombin, rather than plasmin, is one of the major causes of recurrent thrombosis following pharmacologic thrombolysis. Agents that (a) inhibit enzymatic and/or coagulant activity of thrombin, (b) block binding of thrombin to its receptor, and (c) interfere with the generation of thrombin by the prothrombinase complex may compromise haemostasis resulting in haemorrhage. We recently demonstrated that thrombin-induced platelet aggregation is accompanied by cleavage of aggregin, a putative ADP-receptor on the platelet surface, and that these events are indirectly mediated by intracellularly activated calpain expressed on the surface. In this review, we discuss the known mechanisms of thrombin-induced platelet aggregation and suggest relative advantages of potential pharmacological agents, being developed in our laboratory, over those that have been previously developed and tested. These inhibitors selectively prevent aggregation of platelets induced by thrombin by inhibiting calpain expressed on the surface. Moreover, one of these inhibitors which blocks thrombin-induced platelet aggregation does not interfere with other platelet responses mediated by thrombin or platelet aggregation induced by other agonists, such as, ADP, collagen, phorbol myristate acetate and thromboxane A2 mimetics. This selectivity could reduce the chances of perturbing the formation of a haemostatic plug.
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PMID:Reocclusion after thrombolytic therapy: strategies for inhibiting thrombin-induced platelet aggregation. 832 74

Thrombolytic therapy with recombinant tissue plasminogen activator was tested in an embolic stroke model. In rats the internal carotid territory was embolized through the internal carotid artery with 50 microliters thrombin-rich (n = 18), 50 microliters thrombin-poor (n = 17) and 20 microliters thrombin poor (n = 13) suspension of arterial-like microthrombi formed under pressure. Hemispheric cerebral blood flow before and after embolization was measured by intra-arterial 133Xe injection method. Fifteen minutes after embolization 19 animals were treated with tissue plasminogen activator 20 mg kg-1, and 22 animals with saline. Carotid angiography displayed the degree of occlusion of the cerebral arterial supply before and after treatment. Brains were evaluated neuropathologically and infarct volume measured. Cerebral blood flow was reduced 72% after embolization with 50 microliters emboli suspension and 32% after embolization with 20 microliters suspension. The comparison of pre- and post-treatment angiography showed some recanalization in the treated animals, control animals had no recanalization. Thrombolytic therapy reduced the infarct volume from 72.8% to 20.9% of embolized hemisphere volume (p = 0.0037) in the 50-microliters thrombin rich-embolized group, from 22.9 to 9.0 (NS) in the 50-microliters-thrombin-poor-embolized group and from 6.6 to 0.0 (NS) in the 20-microliters-embolized group. One third of treated animals recanalized completely and developed smaller (p = 0.03) infarcts than the non-recanalized. No hemorrhagic complications were observed. Early thrombolytic therapy reduced infarct volume after embolic stroke in this model, this effect was dependent upon recanalization.
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PMID:Reduction of infarct volume by thrombolysis with rt-PA in an embolic rat stroke model. 837 42

Although tissue factor pathway inhibitor (TFPI) plays an essential role in the regulation of blood coagulation, the quantitative changes in its levels in thrombotic disease are still undefined. We compared TFPI activity in ischemic stroke patients and control subjects matched for age and cholesterol level to determine whether TFPI activity is changed in the disease. TFPI activity was significantly lower in the stroke patients (1.01 +/- 0.24 U/ml) than in the control subjects (1.10 +/- 0.16 U/ml). In relation to clinical subtypes of stroke, TFPI activity in atherothrombotic infarction (0.93 +/- 0.19 U/ml) and lacunar infarction (0.99 +/- 0.23 U/ml) was significantly lower than in the control subjects, whereas the level in cardioembolic infarction (1.16 +/- 0.31 U/ml) was not. No relationship could be established between TFPI activity and other haemostatic parameters reflecting the production of thrombin/fibrin and the activation of fibrinolysis. These results may suggest that the moderately lower TFPI activity in stroke patients could be due to atherosclerotic changes rather than to consumptive coagulopathy.
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PMID:Decreased plasma tissue factor pathway inhibitor activity in ischemic stroke patients. 856 Apr 12

Control of thrombin by its inhibition in indications such as myocardial infarction, unstable angina or stroke has been demonstrated to be therapeutically valuable. However restoration of hemostasis by targeting thrombin while avoiding its fellow serine proteinases, (e.g. plasmin, trypsin), remains a challenge of medicinal chemistry. Tripeptide-boronates and -phosphonates with neutral P1 side chains meet these criteria. Development of novel, high yielding chemical routes furnishes a wide range of un-natural P1 functionalities, demonstrating that this indeed is a class effect with selectivity conferred by the uncharged P1 residue. For example N-benzyloxycarbonyl-D-phenylalanylprolyl-1- (3-methoxypropyl) boroglycine ester (1) has a Ki value for thrombin of 7 nM and greater than two order of magnitude higher with all other serine proteinases tested. The ester group determines the kinetics of inhibition by tripeptide phosphonates, with diphenylphosphonates being slow tight binding inhibitors, showing 50% reversibility of inhibition. Therefore this design of inhibitors offers a facile strategic approach to development as thrombin specific pharmaceutical agents.
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PMID:Structure/function aspects of neutral P1 residue peptide inhibitors of thrombin. 856 64

Thrombin inhibitors have been thought to play a pivotal role in myocardial infarct and stroke incidences and their aftermath. Quite some time ago potent synthetic thrombin inhibitors became known based on peptide derivatives D-Phe-Pro-Arg and benzamidine. One of them, fairly well characterised was beta-naphthylsulphonylglycyl-D,L-4-amidino-phenylalanylpiperidi de (NAPAP). NAPAP was prone to being administered intravenously due to its short plasma half life. Drawbacks to this compound such as effects on histamine release and blood pressure may have obstructed its clinical use. Long half life and oral bioavailability would be desirable for prophylactic treatment of thrombotic disorders. We have used NAPAP as a template for new synthetic compounds to improve some characteristics of its profile. For screening purposes we have investigated fairly simple surrogate parameters, aspects that were considered to contribute to pharmacological effects. Potency was correlated to thrombin inhibition, side effects were addressed by specificity toward thrombin as well as reduction in basicity, and plasma half life was considered to be modulated by plasma stability of the compound. Oral bioavailability would be affected by instability during the passage through the gut wall. Chemical introduction of a carboxylic group and exchange of the naphthyl group for 4-methoxy-2,3,6-trimethylphenyl led to a compound that when compared to NAPAP, exhibited a 4-fold increase in thrombin inhibitory activity and a 3-fold increase in trypsin specificity. Plasma stability decreased to 22 h, however, sufficient enough not to play a major role in plasma half life. Gut homogenate stability of the compound has not changed. The potency increase did not translate into a reduction in IC50-values for the coagulation assay aPTT and TT, in contrast to the IC50-values for thrombin-induced platelet aggregation.
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PMID:Synthesis and characterisation of novel thrombin inhibitors based on 4-amidinophenylalanine. 856 67

The carotid sinuses, one of the major sites of baroreceptor innervation, are also a common site of atherosclerotic lesions and platelet aggregation. The goal of the present study was to determine whether platelet activation in carotid sinuses causes reflex-mediated changes in renal sympathetic nerve activity and arterial pressure. Rabbit platelets were isolated, resuspended in Krebs' buffer, and activated by thrombin. Injection of activated platelets (3 x 10(8) platelets/mL) into the vascularly isolated carotid sinuses of anesthetized rabbits essentially eliminated sympathetic nerve activity and acutely decreased mean arterial pressure from 126 +/- 5 to 53 +/- 4 mm Hg (n=16; P < .05). Sympathetic activity and arterial pressure returned to control levels over a period of minutes despite sustained exposure to activated platelets. Injection of U-46619, a thromboxane analogue and vasoconstrictor, into carotid sinuses did not alter sympathetic activity or arterial pressure. However, serotonin (5-hydroxytryptamine [5-HT]), which is known to be released from activated platelets, and the 5-HT3 receptor agonist phenylbiguanide mimicked the effect of platelets. Furthermore, the platelet-induced reflex inhibition of sympathetic activity and hypotension were not altered by the cyclooxygenase inhibitor indomethacin but were attenuated significantly by 5-HT receptor antagonists. Platelet activation inhibited sympathetic activity to 5 +/- 2% of control in the absence of antagonists but to only 35 +/- 11 and 76 +/- 4% of control after selective blockade of 5-HT2 and 5-HT3 receptors with ketanserin and MDL-72222, respectively. The results indicate that (1) platelet activation in carotid sinuses triggers reflex inhibition of sympathetic nerve activity and hypotension; (2) the reflex is not caused by carotid vasoconstriction and is not mediated by prostanoids; and (3) the reflex is mediated by 5-HT acting primarily on 5-HT3 and to a lesser extent on 5-HT2 receptors. We speculate that this reflex may contribute to arterial pressure lability and susceptibility to stroke in patients with carotid atherosclerotic disease.
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PMID:Platelet activation in carotid sinuses triggers reflex sympathoinhibition and hypotension. 861 8

We have reported that cytosolic Ca2+ concentration ([Ca2+]i) is increased in platelets from spontaneously hypertensive rats (SHR) in both basal and thrombin-stimulated conditions. To determine whether the correlation between blood pressure and cellular Ca2+ metabolism exists in stroke-prone SHR (SHRSP), we investigated Ca2+ handling using fura 2 and aggregation response in platelets of 12- to 13-week-old male SHRSP, SHR, and Wistar-Kyoto rats (WKY). Systolic pressure was highest in SHRSP and lowest in WKY (213 +/- 8, 172 +/- 7, and 135 +/- 5 mm Hg, respectively). Basal [Ca2+]i was significantly higher in SHR than WKY (45.9 +/- 4.5 versus 41.2 +/- 4.8 nmol/L, P<.05), and that in SHRSP (40.2 +/- 2.8 nmol/L) was similar to that in WKY. Thrombin (0.1 IU/mL)-stimulated [Ca2+]i rise was greater in SHR and smaller in SHRSP than in WKY in the presence of extracellular Ca2+ (530 +/- 50 and 408 +/- 52 versus 475 +/- 50 nmol/L, respectively; P<.05). The recovery rate from the peak [Ca2+]i response to thrombin was greatest in SHRSP and least in WKY. Ionomycin (5 micromol/L)-stimulated [Ca2+]i rise was similar in WKY, SHR, and SHRSP (731 +/- 97, 743 +/- 88, and 683 +/- 70 nmol/L, respectively). Thrombin-induced maximum platelet aggregation response was higher in SHR and lower in SHRSP than WKY (82 +/- 4 percent and 61 +/- 15 percent versus 73 +/- 6 percent, respectively; P<.05). In contrast to SHR, basal [Ca2+]i in SHRSP was similar to that in WKY, and thrombin-stimulated [Ca2+]i was attenuated. These result suggest that platelet Ca2+ handling differs between SHR substrains and that an increased [Ca2+]i is not obligatory in genetically hypertensive rats.
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PMID:Platelet Ca2+ is not increased in stroke-prone spontaneously hypertensive rats: comparative study with spontaneously hypertensive rats. 864 41

Recent epidemiological studies have suggested that 15 to 30% of all ischemic stroke is comprised of cardioembolic stroke. The presence of intracardiac thrombi might prove to be the most reliable tool when making a diagnosis of cardioembolic stroke, although not always easy to determine even with recent advanced technique. In this study, sensitivities to detect intracardiac thrombi of transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), cardiac-enhanced CT (CCT) and scintigraphy with indium-111-tropolone-labelled platelets (PSG) were compared, in order to provide a relevant guideline for the diagnosis of intracardiac thrombi in 83 patients suspected of cardioembolic stroke. Also studied was the correlation of intracardiac thrombi with activation of platelets and coagulation-fibrinolysis through performing various hemostatic tests in order to investigate their utility for the evaluation of in situ thrombosis or prothrombotic state in the heart chamber. Detection rates of intracardiac thrombi were 35% in TEE, 26% in CCT, 19% in PSG, and 11% in TTE. There was a significant difference in the sensitivity between TEE and TTE (p < 0.05). Left atrial thrombi were frequently detected in TEE (4 out of 5 patients) and CCT (7 out of 10), while they were found less in PSG (2 out of 4) an TTE (4 out of 10). Thrombi in the left appendage were visualized in 3 out of 3 by TEE, while only in 1 out of 3 by PSG, 1 out of 4 by TTE and 1 out of 4 by CCT. Left ventricular thrombi; CCT (3 out of 3), TTE (2 out of 3), PSG (1 out of 1); TEE was not performed since this technique could not be expected to provide high-quality images of left ventricular thrombi. Thus, left atrial thrombi were considered to be more sensitively detected by TEE and CCT, left appendage thrombi by TEE, and left ventricular thrombi by TTE and CCT. There was no patient in whom an intracardiac thrombus was visualized by PSG alone. On the basis of the results above, we propose the following guideline for the detection of intracardiac thrombi in patients presented with cardioembolic stroke. First, TTE and CCT appear to be relevant for screening tests because of simple and non-invasive techniques. These two tools might be sensitive enough to find left ventricular thrombi. Second, TEE should be recommended when a thrombus is suspected in the left atrium or appendage. Finally, PSG may be used to determine the activity of the thrombus, according to its necessity. Among the patients having intracardiac thrombi, frequently observed was the increase of beta-thromboglobulin, platelet factor 4, platelet lysis, thrombin-antithrombin III complex, D-dimer in 67%, 75%, 71%, 80% and 80%, respectively, as well as the shortening of platelet survival in 100%, while anrithrombin III was reduced in only 38%. In addition, when hemostatic abnormalities were compared between positive and negative groups of intracardiac thrombi, the shortening of platelet survival (p < 0.0001), the increase of platelet lysis, and the increase of D-dimer (p < 0.04) were more frequent in the positive group than in the negative group. These results indicate that the findings of activation of platelets and coagulation-fibrinolysis, except for the reduction of antithrombin III, especially the findings of platelet consumption and lysis as well as fibrinolysis activation are useful as sensitive parameters of in situ thrombosis or prothrombotic state, which may lead to the formation of intracardiac thrombi.
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PMID:[Diagnosis of intracardiac thrombi by various imaging techniques and activation of platelets and coagulation-fibrinolysis in patients with cardioembolic stroke]. 874 45

Cerebrovascular accidents are rare but well documented in patients with Crohn's disease. Up to 10% of hypercoagulable state manifestations reported in association with inflammatory bowel disease are ischemic strokes. However, no clear mediating factor has thus far been suggested. A 44-year-old woman with Crohn's disease for 25 years developed a left temporal stroke associated with anticardiolipin antibody and lupus anticoagulant suggesting antiphospholipid syndrome. A thorough evaluation did not reveal any other risk factor for ischemic stroke. No possible sources of emboli were found in the carotids and heart, and no deficiencies of protein C and activated protein C, protein S, and anti-thrombin III leading to hypercoagulable state were present. There may be a possible association between antiphospholipid syndrome and hypercoagulable state in Crohn's disease.
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PMID:Antiphospholipid syndrome manifested by ischemic stroke in a patient with Crohn's disease. 874 56

Thrombin-induced phosphorylation of 47 kDa protein (P47) in platelets, a substrate of protein kinase C (PKC), was defective in stroke-prone spontaneously hypertensive rats (SHRSP) (Hypertens. 14, 304-315, 1989). Platelet PKC from SHRSP and Wistar Kyoto rats (WKY) was partially purified and Ca(2+)-sensitivity of PKC activity was examined to understand the defect in the protein phosphorylation. When the platelets from SHRSP and WKY were homogenized in a buffer containing 10 mM EGTA and 2 mM EDTA, approx. 80% of PKC was in the cytosol fraction. PKC in this fraction was purified by DE52 and hydroxyapatite column chromatography. Both platelet PKC preparations contained only PKC-alpha, and there was no significant difference in the Ca(2+)-dependency of activity between them. When the platelets from SHRSP and WKY were homogenized in a buffer containing 10 microM CaCl2, 90% of PKC was found to be bound to the membrane. PKC was extracted from the membrane with a buffer containing 2.5 mM EGTA and 2.5 mM EDTA, and purified by DE52 column chromatography. PKC from WKY platelets eluted as a single peak whereas that from SHRSP platelets eluted as two peaks (peak 1 and peak 2). Ca(2+)-sensitivity of peak 1 PKC was much lower than that of WKY PKC. In contrast, the Ca(2+)-sensitivity of peak 2 PKC appeared to be slightly higher than that of WKY PKC. The specific activity of peak 2 PKC was 4% to 5% of that of peak 1 and WKY PKC. These results suggest that there are two different types of PKC, normal and low Ca(2+)-sensitive in SHRSP platelets. Defective P47 phosphorylation in SHRSP platelets might be attributable to the occurrence of this low Ca(2+)-sensitive PKC.
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PMID:The differences in Ca(2+)-sensitivity of protein kinase C in platelets from Wistar Kyoto rat and stroke-prone spontaneously hypertensive rat. 877 2


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